Non–Small Cell Lung Cancer

EPIDEMIOLOGY

Incidence for NSCLC in the United States is second to prostate

cancer in men and breast cancer for women. Lung cancer is

the leading cause of death relative to all of the other cancers.

As with most solid tumors, survival is better for patients diagnosed with early stage disease than it is for those with more

advanced disease. However, for many patients the disease often

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2211Lung Cancer Chapter 94

goes undetected either due to the lack of noticeable symptoms

or because they may be masked by concurrent diseases such as

chronic obstructive pulmonary disease (COPD), which can cause

similar symptoms.

PATHOPHYSIOLOGY

NSCLC tumorigenesis is a multistep process in which neoplastic

tissue arises from bronchial epithelium. These cells, which form

the inner lining of bronchial tissue, develop genetic lesions to

protooncogenes and tumor suppressor genes, resulting in the

dysregulation of key molecular signaling pathways. As a result,

cellular proliferation occurs and responsiveness to apoptotic signaling is often diminished. Eventually, accumulation of additional

genetic abnormalities can influence the cell’s ability to metastasize, resulting in the spread of tumorous tissue locally or to more

distant sites in the lymph nodes and organs.

Non–small cell lung tumors are classified further according

to tumor tissue histology. The three major histiologic types

include squamous cell carcinoma, adenocarcinoma, and large

cell carcinomas. Although these different variants were identified

several decades ago, it was only recognized recently that they

differ in their sensitivities to certain chemotherapeutic agents.

These three may be subcategorized further, and other variants

of NSCLC also exist; however, discussion in this chapter will

be limited to these three. The adenocarcinomas and large cell

carcinomas are commonly grouped together as nonsquamous

carcinomas. These tumors commonly arise in the periphery of

the lung and the smaller airways. After various periods of growth

in the lung parenchyma or bronchial wall, these primary tumors

invade the vascular and lymphatic system, enabling metastases

to regional lymph nodes and more distant sites.1

RISK FACTORS AND CLINICAL PRESENTATION

There are several risk factors for developing lung cancer, but

the biggest factor is cigarette smoking, which is estimated to

increase the risk by up to 30-fold. The prevalence of smoking

peaked in the early 1960s just prior to the Surgeon General’s

first report regarding the harms of smoking. Since that time,

the per capita cigarette consumption in the United States has

steadily decreased up to the year 2000, for which the latest data

are available. Death rates for both men and women followed

this trend. For men, deaths due to lung cancer peaked in the

1980s and has since steadily decreased. For women, deaths due

to lung cancer appear to have reached a plateau around the year

2000. The most recent Surgeon General’s report emphasizes the

relation between exposure to secondhand smoke and increased

risk for lung cancer. The report also addresses the risks associated with newer types of cigarettes developed by the tobacco

industry. Other risk factors include cigar and pipe smoking, occupational and environmental exposures, radon, asbestos, certain

metals such as chromium and cadmium, various organic chemicals, radiation, air pollution, history of tuberculosis, and genetic

factors. The latter appears to be related to those who exhibit the

disease early in life. The probability for exhibiting invasive lung

cancer increases with age and peaks during the seventh decade of

life. Lifetime, the probability is 1 in 13 men and 1 in 16 women.2–5

The disease is detected either because a person presents with

signs and symptoms commonly associated with lung cancer or by

chance, when the patient is under evaluation for other disorders

or procedures. Selected signs and symptoms are listed in Table

94-1, but vary widely between patients according to tumor size,

stage, and location.

DIAGNOSIS

If a malignancy comes under consideration, a computed tomography (CT) or positron emission tomography (PET)–CT scan of

TABLE 94-1

Common Selected Signs and Symptoms for Lung Cancer

Cough

Hemoptysis

Wheeze

Dyspnea

Pain (e.g., chest wall)

Obstruction of vital structures (e.g., esophagus, superior vena cava)

Symptoms are highly dependent on tumor size, location within the chest cavity,

and presence of metastases.

the abdomen and thoracic region is usually performed to identify any possible primary lesions and to look for possible metastases to lymph nodes and other organs or contralateral lung.

If located, a pathological evaluation is performed to confirm

the diagnosis. Magnetic resonance imaging (MRI) to the head

may be ordered if brain metastases are suspected. Preoperatively,

specimens may be obtained through methods such as bronchial

brushings, bronchial washings, fine needle aspiration biopsy, core

needle biopsy, endobronchial biopsy, and transbronchial biopsy.

Mediastinal lymph nodes are also sampled via mediastinoscopy

to assess staging. If surgery is performed, specimens are evaluated during the procedure to determine the resection margin

status, diagnose incidental nodules discovered during surgery,

and sampling of regional lymph nodes. Post operative evaluation provides pathology characteristics necessary for classifying

tumor type and staging.1

Staging is performed to determine prognosis and to guide

treatment decision-making. In general, the prognosis declines

with increasing disease stage at initial diagnosis. Five-year overall

survival rates are 53% for patients with disease that is locally

limited, 24% for regional, and 4% for metastatic disease. For all

stages, five-year overall survival has only marginally improved

over the last 30 years to 16%. Unfortunately, the disease has

already metastasized in greater than 50% of patients upon initial

presentation. Clearly, earlier detection and better treatments are

needed.5

Staging classification is reliant on anatomic characteristics,

and has recently been updated by the International Association

for the Study of Lung Cancer (IASLC) and adopted by the American Joint Committee on Cancer staging. Even though clinicians

are placing more importance on molecular markers such as epidermal growth factor receptor (EGFR) mutations and tumor

histology, the revised system still relies strictly on the TNM system of staging. Shown in Table 94-2 are the definitions for the T,

N, and M descriptors in the staging of NSCLC. Lymph nodes are

classified according to anatomic location (station).

For a visual of a lymph node map, go to

http://thepoint.lww.com/AT10e.

Once these descriptors are determined for a patient, stage is

determined according to the criteria listed in Table 94-3.6,7

OVERVIEW OF TREATMENT

Surgery, radiation, and systemic therapy (i.e., chemotherapy and

targeted therapy) are all treatment modalities used in the treatment of NSCLC. If caught in the early stages of the disease,

surgery offers the best hope for cure. Non–small cell lung tumors

are generally slow growing; however, chemotherapy is associated with enhanced survival depending on the stage of disease.

The remaining discussion of NSCLC in this chapter will outline

2212Section 17 Neoplastic Disorders

TABLE 94-2

Definitions for T, N, M Descriptors in the IASLC Staging Classificationa

TNM Descriptions Subgroupb

T (Primary Tumor)

T0 No primary tumor

T1 Tumor ≤3 cmc , surrounded by lung or visceral pleura, not more proximal than the lobar bronchus

T1a Tumor ≤2 cmc T1a

T1b Tumor >2 but ≤3 cmc T1b

T2 Tumor >3 but ≤7 cmc or tumor with any of the followingd :

Invades visceral pleura, involves main bronchus ≥2 cm distal to the carina, atelectasis/obstructive

pneumonia extending to hilum but not involving the entire lung

T2a Tumor >3 but ≤5 cmc T2a

T2b Tumor >5 but ≤7 cmc T2b

T3 Tumor >7 cmc T3>7

or directly invading chest wall, diaphragm, phrenic nerve, mediastinal pleura, parictal pericardium, T3tav

or tumor in the main bronchus <2 cm distal to the carinac , T3Centr

or atelectasis/obstructive pneumonitis of entire lung, T3Centr

or separate tumor nodule(s) in the same lobe T3Satell

T4 Tumor of any size with invasion of: heart, great vessels, tracheae , recurrent laryngeal nerve, esophagus,

vertebral body, or carinae ; or separate tumor nodule(s) in a different ipsilateral lobe

T4Inv

N (Regional Lymph Nodes)

N0 No regional node metastasis

N1 Metastasis in ipsilateral peribronchial and/or perihilar lymph nodes and intrapulmonary nodes, including

involvement by direct extension

N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)

N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or

supraclavicular lymph node(s)

M (Distant Metastasis)

M0 No distant metastasis

M1a Separate tumor nodule(s) in a contralateral lobe; M1aContr,Nod

or tumor with pleural nodules or malignant pleural dissemination f M1aPl,Dissem

M1b Distant metastasis M1b

Special Situations:

TX, NX, MX T, N, or M status not able to be assessed

Tis Focus of in situ cancer Tis

T1c Superficial spreading tumor of any size but confined to the wall of the trachea or mainstem bronchus T1ss

aReflects the IASLC Staging Committee’s recommendations and not necessarily the UICC 7th Edition Staging System.

bThese subgroup labels are not defined in the IASLC publications, but are added here to facilitate a clear discussion. Goldstraw et al. J Thorac Oncol 2007;2:706–714;

Rami-Porta et al. J Thorac Oncol 2007;2:593; Postmus et al. J Thorac Oncol 2007;2:686; Rusch et al. J Thorac Oncol 2007;2:603. c In greatest dimension.

dT2 tumors with these features are classified as T2a if ≤5 cm. eThe uncommon superficial spreading tumor in central airways is classified as T1.

f Pleural effusions are excluded that are cytologically negative, nonbloody, transdative, and clinically judged not to be due to cancer.

IASLC, International Association for the Study of Lung Cancer; TNM, tumor, node, metastasis.

Reprinted with permission from Detterbeck FC et al. Anatomy, biology and concepts, pertaining to lung cancer stage classification. J Thorac Oncol. 2009;4:437.

the key aspects in the treatment of early and late stages of the

disease.

Early-Stage Non–Small Cell Lung Cancer

CASE 94-1

QUESTION 1: A 69-year-old male patient, J.W., was found

to have a 3-cm nodule on a chest x-ray done prior to an elective cataract surgery. The patient was a lifelong cigarette

smoker, having started smoking in his early 20s, approximately one pack of cigarettes per day. He quit smoking

9 years ago. What screening methods might be available

to detect the disease in asymptomatic patients? What risk

factors does J.W. have for lung cancer?

There are currently no screening methods available to detect

early stage lung cancer in asymptomatic patients. Survival would

likely improve if suitable methods could be identified, because

overall survival is much better when detected early. The National

Lung Screening Trial (NLST) is a randomized study of screening

methods to reduce deaths from lung cancer by detecting cancers

at relatively early stages. Thus far, the NLST has enrolled about

53,000 men and women with at least 30 pack-years of smoking history without signs and symptoms of lung cancer. They

have been randomly assigned to receive three annual screens

with either low-dose helical CT or standard chest x-ray. Initial

results appear promising: Researchers report 20% fewer lung

cancer deaths among trial participants screened with low-dose

helical CT relative to chest x-ray. Final data analyses are not yet

complete and application of these results are not yet clear. For

example, it is not known how many cigarettes and for how long

2213Lung Cancer Chapter 94

TABLE 94-3

Stage Groups in the IASLC Staging Classificationa

Stage Group T N M

I

Ia T1a,b N0 M0

Ib T2a N0 M0

II

IIa T1a,b N1 M0

T2a N1 M0

T2b N0 M0

IIb T2b N1 M0

T3 N0 M0

III

IIIa T1–3 N2 M0

T3 N1 M0

T4 N0,1 M0

IIIb T4 N2 M0

T1–4 N3 M0

IV TAny NAny M1a,b

aReflects the IASLC Staging Commitee’s recommendations and not necessarily

the UICC 7th edition staging system.

IASLC, International Association for the Study of Lung Cancer; TNM, tumor

node metastasis.

Reprinted with permission from Detterbeck FC et al. Anatomy, biology and

concepts, pertaining to lung cancer stage classification. J Thorac Oncol. 2009;4:437.

one would need to smoke to warrant annual screening, and the

question of how long does one need screening (i.e., 10 years,

20 years, lifetime). This could potentially represent several scans

and, therefore, a large radiation burden. Hence, practice is not

expected to change immediately.8–10

The probability for exhibiting the disease increases with age,

and J.W.’s age is close to the median age of peak incidence. Men

also have a slightly higher risk than women as discussed previously. Smoking is the largest risk factor for lung cancer development; however, what if a person stops smoking? Does the risk

decrease with time? These questions are important for health

care providers to address if they are encouraging smoking cessation for their patients. In J.W.’s case, he stopped 9 years ago, so

what impact would this smoking history have on development

of the disease? In general, people who stop smoking, even well

into middle age, avoid almost 90% of the risk attributable to

tobacco. Shown in Table 94-4 are data demonstrating the relation between the age at which a person stops smoking and the

cumulative percent risk (at age 75) for developing lung cancer.11

J.W. stopped when he was approximately 50 years old; therefore,

based on this table, the cumulative risk would approach 6% if he

were 75 years old. Because he is 60 years old, his risk would be

decreased but not to the extent that it would if a longer period

of time had elapsed. If he were still smoking the risk would be

expected to be closer to 15% to 16%. Hence, smoking cessation

is an effective means for lowering the risk over time. He smoked

TABLE 94-4

Cumulative Risk (%) of Death from Lung Cancer at Age

75 Years

Smoking Status Risk at Age 75

Lifelong nonsmoker <1

Stopped at age 30 <2

Stopped at age 40 3

Stopped at age 50 6

Stopped at age 60 10

Continuing smoker 16

for approximately 25 to 30 pack-years, so the total number of

cigarettes would also increase his risk. According to data from

the same studies, risk of disease for a one pack per day smoker

would be approximately twice that of someone who smoked less

than a half pack per day. Survival from the disease is also better

for non-smokers than for smokers.11,12

Frequently, patients will experience remorsefulness for having

smoked, but it is never possible to attribute one’s disease to a single factor such as smoking. In fact, 90% of smokers never exhibit

the disease. Further, 15% of men and 53% of all women with lung

cancer worldwide are never-smokers.13 This would suggest other

factors such as genetics are associated with the development of

the disease. Three independent genome-wide association studies

(GWAS) showed that polymorphic variation (single nucleotide